Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC

Autor: Ricardo Sánchez-Prieto, Javier Hernadez Losa, Pedro Melgar-Rojas, Juan Luis Callejas-Valera, Santiago Ramón y Cajal, Antonio Fernández-Aramburo, Eva María Galán-Moya, María Llanos Valero, Mayte Salcedo, Miguel Angel de la Cruz-Morcillo
Jazyk: angličtina
Rok vydání: 2011
Předmět:
MAPK/ERK pathway
Lung Neoplasms
MAPK signaling cascades
Cell Survival
MAP Kinase Kinase 3
p38 mitogen-activated protein kinases
Cell
Cancer Treatment
lcsh:Medicine
Antineoplastic Agents
MAP Kinase Kinase 6
Signal transduction
Biology
p38 Mitogen-Activated Protein Kinases
Biochemistry
Gene Expression Regulation
Enzymologic
Lung and Intrathoracic Tumors
Molecular cell biology
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Basic Cancer Research
medicine
Humans
lcsh:Science
Cisplatin
Gene knockdown
Multidisciplinary
lcsh:R
Signaling cascades
Cancers and Neoplasms
Chemotherapy and Drug Treatment
Non-Small Cell Lung Cancer
Cell biology
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
Drug Resistance
Neoplasm
Cell culture
Medicine
Phosphorylation
RNA Interference
lcsh:Q
Research Article
medicine.drug
Zdroj: PLoS ONE, Vol 6, Iss 12, p e28406 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.
Databáze: OpenAIRE
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